The respiratory responses to inspiratory flow-resistive loading during hypercapnia has been studied in normal subjects and subjects on chronic methadone maintenance. Responses were determined before and after oral intake of methadone (0.2 mg/kg in normal subjects, their usual daily dose of methadone in subjects on methadone maintenance). We have found that methadone depresses both the responses to hypercapnia and the effort generated to overcome the effects of an inspiratory resistence in normal-non-addicted subjects. Subjects on methadone maintenance had similar responses to hypercapnia and to the inspiratory resistance as the normal subjects prior to intake of methadone. However, after methadone, these subjects exhibited no significant changes in responses compared to their control values indicating the development of full tolerance to the drug.